Jun Sang Bae

Tumor infiltrating PD1-positive lymphocytes and the expression of PD-L1 predict poor prognosis of soft tissue sarcomas.

Recently, the possibility of PD1 pathway-targeted therapy has been extensively studied in various human malignant tumors. However, no previous study has investigated their potential application for soft-tissue sarcomas (STS). In this study, we evaluated the clinical impact of intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression in tumor cells in 105 cases of STS. Intra-tumoral infiltration of PD1-positive lymphocytes and PD-L1 expression were seen in 65% and 58% of STS, respectively. Both PD1-positivity and PD-L1 expression were significantly associated with advanced clinicopathological parameters such as higher clinical stage, presence of distant metastasis, higher histological grade, poor differentiation of tumor, and tumor necrosis. Moreover, both PD1-positivity and PD-L1 positivity were independent prognostic indicators of overall survival (OS) and event-free survival (EFS) of STS by multivariate analysis. In addition, the combined pattern of PD1- and PD-L1-positivity was also an independent prognostic indicator for OS and EFS by multivariate analysis. The patents with a PD1+/PD-L1+ pattern had the shortest survival time. In conclusion, this study is the first to demonstrate that the infiltration of PD1 positive lymphocytes and PD-L1 expression in STS cells could be used as novel prognostic indicators for STS. Moreover, the evaluation of PD1- and PD-L1-positivity in STS is also available as possible criteria for selection of patients suitable for PD1-based immunotherapy.

Expression of SIRT1 and DBC1 Is Associated with Poor Prognosis of Soft Tissue Sarcomas

Recently, the roles of SIRT1 and deleted in breast cancer 1 (DBC1) in human cancer have been extensively studied and it has been demonstrated that they are involved in many human carcinomas. However, their clinical significance for soft-tissue sarcomas has not been examined. In this study, we evaluated the expression and prognostic significance of the expression of SIRT1, DBC1, P53, β-catenin, cyclin D1, and KI67 in 104 cases of soft-tissue sarcomas. RESULTS: Immunohistochemical expression of SIRT1, DBC1, P53, β-catenin, and cyclin D1 were seen in 71%, 74%, 53%, 48%, and 73% of sarcomas, respectively. The expression of SIRT1, DBC1, P53, β-catenin, and cyclin D1 were significantly correlated with advanced clinicopathological parameters such as higher clinical stage, higher histological grade, increased mitotic counts, and distant metastasis. The expression of SIRT1, DBC1, P53, β-catenin, cyclin D1, and KI67 were significantly correlated with each other and positive expression of all of these predicted shorter overall survival and event-free survival by univariate analysis. Multivariate analysis revealed the expression of SIRT1 as an independent prognostic indicator for overall survival and event-free survival of sarcoma patients. In conclusion, this study demonstrates that SIRT1- and DBC1-related pathways may be involved in the progression of soft-tissue sarcomas and can be used as clinically significant prognostic indicators for sarcoma patients. Moreover, the SIRT1- and DBC1-related pathways could be new therapeutic targets for the treatment of sarcomas.

Acetylation status of P53 and the expression of DBC1, SIRT1, and androgen receptor are associated with survival in clear cell renal cell carcinoma patients

Aims: Recently, the important role of silent mating type information regulation 2 homolog 1 (SIRT1) and deleted in breast cancer 1 (DBC1) in human cancer has been extensively studied and their role has been closely related with the control of P53 and androgen receptor (AR) functions. However, their role in clear cell renal cell carcinoma (CRCC) is still unknown. Methods: We evaluated the expression of SIRT1, P53, acetylated-P53, DBC1 and AR and their prognostic significance in 200 CRCC patients. Results: The expression of SIRT1, P53, DBC1, and AR significantly correlated with each other and all of them predicted shorter overall survival (OS), relapse-free survival (RFS), and cancer-specific survival (CSS). In contrast, the expression of acetylated-P53 predicted favourable OS, RFS, and CSS. Combined expression pattern of acetylated-P53 and P53 (Ac-P53/P53) also closely correlated with survival of CRCC patients. Multivariate analysis revealed DBC1, acetylated-P53, and Ac-P53/P53 expression as independent prognostic indicators for OS and RFS, and Ac-P53 expression as an independent prognostic indicator for CSS. Conclusions: This study demonstrates that the acetylation status of P53 and the expression of SIRT1, DBC1, and AR could be new prognostic indicators for CRCC and suggest that SIRT1-P53 and DBC1-AR related pathways could be new therapeutic targets for the treatment of CRCC.

Expression of nerve growth factor and heme oxygenase-1 predict poor survival of breast carcinoma patients

BackgroundNerve growth factor (NGF) is a neurotrophin and has been suggested to induce heme oxygenase-1 (HO1) expression. Although the role of HO1 in tumorigenesis remains controversial, recent evidence suggests NGF and HO1 as tumor-progressing factors. However, the correlative role of NGF and HO1 and their prognostic impact in breast carcinoma is unknown.MethodsWe investigated the expression and prognostic significance of the expression of NGF and HO1 in 145 cases of breast carcinoma.ResultsImmunohistochemical expression of NGF and HO1 was observed in 31% and 49% of breast carcinoma, respectively. The expression of NGF and HO1 significantly associated with each other, and both have a significant association with histologic grade, HER2 expression, and latent distant metastasis. The expression of NGF and HO1 predicted shorter overall survival of breast carcinoma by univariate and multivariate analysis. NGF expression was an independent prognostic indicator for relapse-free survival by multivariate analysis. The combined expression pattern of NGF and HO1 was also an independent prognostic indicator of overall survival and relapse-free survival. The patients with tumors expressing NGF had the shortest survival and the patients with tumor, which did not express NGF or HO1 showed the longest survival time.ConclusionsThis study has demonstrated that individual expression of NGF or HO1, and the combined NGF/HO1 expression pattern could be prognostic indicators for breast carcinoma patients.

CK2α phosphorylates DBC1 and is involved in the progression of gastric carcinoma and predicts poor survival of gastric carcinoma patients

CK2α has diverse effects on the tumorigenesis owing to its kinase activity, which phosphorylates various proteins involved in tumorigenesis. We, therefore, investigated the expression and role of CK2α in the phosphorylation of deleted in breast cancer 1 (DBC1) in gastric carcinomas. We used 187 gastric carcinomas and human gastric cancer cells to investigate the roles and relationship between CK2α and DBC1 in gastric carcinomas. Positive expression of CK2α and phospho‐DBC1 predicted shorter overall survival and relapse‐free survival by univariate analysis. Especially, CK2α expression was an independent prognostic indicator for gastric carcinoma patients. In gastric carcinoma cells, CK2α was bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2α was evidenced by co‐immunoprecipitation of CK2α and DBC1 in a GST pull‐down assay, an in vitro kinase assay, and immunofluorescence staining. Inhibition of both CK2α and DBC1 decreased proliferation and invasive activity of cancer cells. Decreased migration and invasive activity was associated with a downregulation of MMP2, MMP9 and the epithelial–mesenchymal transition. A mutation at the phosphorylation site of DBC1 also downregulated the signals related with the epithelial–mesenchymal transition. Our study demonstrated that CK2α is an independent prognostic indicator for gastric carcinoma patients and is involved in tumorigenesis by regulating the phosphorylation of DBC1. In addition, the blocking of CK2α and DBC1 inhibited the proliferation and invasive potential of gastric cancer cells. Therefore, our study suggests that CK2α–DBC1 pathway might be a new therapeutic target for the treatment of gastric carcinoma.

DBC1/CCAR2 is involved in the stabilization of androgen receptor and the progression of osteosarcoma

Deleted in breast cancer 1 (DBC1/CCAR2) is a protein of interest because of its diverse roles in tumorigenesis and its possible role as an androgen receptor (AR) co-activator. However, there are limited studies on the role of DBC1 in osteosarcoma. Therefore, we investigated the role of DBC1 and AR and their relationship in osteosarcoma. Immunohistochemical expression of DBC1 and AR was significantly associated with higher clinical stage and higher histologic grade, and predicted shorter survival. Especially, DBC1 expression was an independent prognostic indicator of overall survival (p = 0.005) and relapse-free survival (p = 0.004) by multivariate analysis. In osteosarcoma cell lines, U2OS and SaOS2, the knock down of DBC1 and AR with siRNA significantly reduced cellular proliferation and inhibited proliferation-related signaling. In addition, the knock down of DBC1 and AR decreased the invasion activity and inhibited invasion-related signaling of osteosarcoma cells. Interestingly, DBC1 affects the stabilization of AR protein via a mechanism involving the ubiquitination of AR. Proteosome-mediated degradation and poly-ubiquitination of AR were increased with the knock-down of DBC1. In conclusion, this study has shown that DBC1 is involved in the stabilization of AR protein and DBC1-AR pathways might be involved in the progression of osteosarcoma.

The role of serum response factor in hepatocellular carcinoma: an association with matrix metalloproteinase.

Serum response factor (SRF) regulates tran-scription of immediate early genes and triggers proliferation, migration and differentiation in several types of cells. Matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases, play a crucial role in tumor invasion and metastasis. However, expression of SRF and its association with MMPs in hepatocellular carcinoma (HCC) have not been elucidated. We examined the expression levels of SRF, MMP-2 and MMP-9 in HCC tissues using Western blot assay. We also examined the effect of SRF on MMP expression and enzyme activity in HCC by transfection of SRF cDNA in HLE cells. Protein expression of SRF, MMP-2 and MMP-9 showed a significant increase in HCC tissues, compared with those of corresponding non-tumor tissues. High SRF expressing HCC tissues showed higher levels of expression of MMP-2 and MMP-9, compared with low SRF expressing HCC tissues. In addition, overexpression of SRF in HLE cells led to increased levels of expression of mRNA and protein, as well as increased enzyme activity of MMP-2 and MMP-9. Overexpression of SRF also led to significantly enhanced migration of HLE cells. These results suggest that overexpression of SRF in HCC may play an important role in tumor cell migration and invasion through upregulation of MMP-2 and MMP-9.

Clinicopathologic study on combined hepatocellular carcinoma and cholangiocarcinoma: with emphasis on the intermediate cell morphology.

Combined hepatocellular carcinoma and cholangiocarcinoma (combined HCC-CC) is a rare subtype of primary liver cancer. We investigated the histopathologic features of transitional or intermediate areas in 21 combined HCC-CCs and immunophenotypes using different hepatic progenitor cell markers (CK7, CK19, c-kit, NCAM, and EpCAM). Major histologic findings of transitional or intermediate areas of 21 combined HCC-CCs included strands/trabeculae of small, uniform, oval-shaped cells with scant cytoplasm and hyperchromatic nuclei embedded within an abundant stroma, small cells with an antler-like anastomosing pattern, and solid nests of intermediate hepatocyte-like cells surrounded by small cells in periphery, in order of frequency. The intermediate area of one tumor was composed predominantly of spindle cells arranged in short fascicles. Immunophenotype of tumor cells with intermediate morphology suggested a progenitor cell origin for this tumor. Clinical findings of combined HCC-CC showed a closer resemblance with those of HCC than those of CC. In univariate analysis, tumor size, TNM stage, and serum alpha-fetoprotein levels showed a significant association with poor patient survival. Serum alpha-fetoprotein level was an independent prognostic indicator in multivariate analysis. In conclusion, an awareness of the clinicopathologic features, specifically the various morphologic features of intermediate areas in this tumor, is essential for prevention of potential misdiagnosis as another tumor.

Expressions of E-cadherin, Cortactin and MMP-9 in Pseudoepitheliomatous Hyperplasia and Squamous Cell Carcinoma of the Head and Neck: Their Relationships with Clinicopathologic Factors and Prognostic Implication

Background E-cadherin, cortactin, and matrix metalloproteinase (MMP)-9 have roles in tumor development or progression, but their expression has not been fully investigated in pseudoepitheliomatous hyperplasia (PEH) and squamous cell carcinoma (SCC) of the head and neck. Methods We evaluated the immunohistochemical expression of E-cadherin, cortactin, and MMP-9 in 29 cases of PEH and 97 cases of SCC. Additionally, we evaluated their relationship with clinicopathologic factors and prognostic implications in SCC. Results Thirty-five cases of SCC showed reduced expression of E-cadherin, whereas none of the PEH did. A total of 20 cases and 11 cases of SCC were immunoreactive for cortactin and MMP-9, respectively, whereas none of the PEH did. In SCC, reduced expression of E-cadherin was correlated with cortactin expression and invasion depth. Cortactin expression was correlated with differentiation, T classification, and recurrence and/or metastasis. MMP-9 expression was correlated with invasion depth. Cortactin expression was correlated with poor overall survival and relapse-free survival and it was an independent prognostic factor. Conclusions The reduced expression of E-cadherin and the expression of cortactin may be helpful for the differential diagnosis of PEH and SCC. Furthermore, cortactin expression in association with reduced E-cadherin expression is correlated with poor prognosis in SCC.

Expression of DNA Damage Response Molecules PARP1, γH2AX, BRCA1, and BRCA2 Predicts Poor Survival of Breast Carcinoma Patients

BACKGROUND: Poly(ADP-ribose) polymerase 1 (PARP1), γH2AX, BRCA1, and BRCA2 are conventional molecular indicators of DNA damage in cells and are often overexpressed in various cancers. In this study, we aimed, using immunohistochemical detection, whether the co-expression of PARP1, γH2AX, BRCA1, and BRCA2 in breast carcinoma (BCA) tissue can provide more reliable prediction of survival of BCA patients. MATERIALS AND METHODS: We investigated immunohistochemical expression and prognostic significance of the expression of PARP1, γH2AX, BRCA1, and BRCA2 in 192 cases of BCAs. RESULTS: The expression of these four molecules predicted earlier distant metastatic relapse, shorter overall survival (OS), and relapse-free survival (RFS) by univariate analysis. Multivariate analysis revealed the expression of PARP1, γH2AX, and BRCA2 as independent poor prognostic indicators of OS and RFS. In addition, the combined expressional pattern of BRCA1, BRCA2, PARP1, and γH2AX (CSbbph) was an additional independent prognostic predictor for OS (P < .001) and RFS (P < .001). The 10-year OS rate was 95% in the CSbbph-low (CSbbph scores 0 and 1) subgroup, but that was only 35% in the CSbbph-high (CSbbph score 4) subgroup. CONCLUSION: This study has demonstrated that the individual and combined expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 could be helpful in determining an accurate prognosis for BCA patients and for the selection of BCA patients who could potentially benefit from anti-PARP1 therapy with a combination of genotoxic chemotherapeutic agents.